- Metabolism study and biological evaluation of bosentan derivatives
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Bosentan, the first-in-class drug used in treatment of pulmonary arterial hypertension, is principally metabolized by the cytochromes P450, and it is responsible for cytochromes induction and drug-drug interaction events with moderate to severe consequences. A strategy to reduce drug-drug interactions consists of increasing the metabolic stability of the perpetrator, and fluorinated analogues are often designed to block the major sites of metabolism. In this paper bosentan analogues were synthesized, and their metabolism and biological activity were evaluated. All synthesized compounds showed an improved metabolic stability towards CYP2C9, with one maintaining a moderate antagonist effect towards the ETA receptor.
- Lepri, Susan,Goracci, Laura,Valeri, Aurora,Cruciani, Gabriele
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p. 658 - 670
(2016/07/06)
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- PYRROLIDINYL SULFONE RORGAMMA MODULATORS
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Described are RORγ modulators of the formula (I), or stereoisomers, tautomers, pharmaceutically acceptable salts, solvates, or prodrugs thereof, wherein all substituents are defined herein. Also provided are pharmaceutical compositions comprising the same. Such compounds and compositions are useful in methods for modulating RORγ activity in a cell and methods for treating a subject suffering from a disease or disorder in which the subject would therapeutically benefit from modulation of RORγ activity, for example, autoimmune and/or inflammatory disorders.
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Paragraph 0703-0704
(2015/07/15)
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- Cathepsin cysteine protease inhibitors
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This invention relates to a novel class of compounds which are cysteine protease inhibitors, including but not limited to, inhibitors of cathepsins K, L, S and B. These compounds are useful for treating diseases in which inhibition of bone resorption is i
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Page/Page column 18
(2010/11/08)
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- Substituted 4-(2,2-Diphenylethyl)pyridine-N-oxides as phosphodiesterase-4 inhibitors: SAR study directed toward the improvement of pharmacokinetic parameters
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A detailed SAR study directed toward the optimization of pharmacokinetic parameters for analogues of L-791,943 is reported. The introduction of a soft metabolic site on this structure permitted the identification of L-826,141 as a potent phosphodiesterase type 4 (PDE4) inhibitor that is well absorbed and that presents a shorter half-life than L-791,943 in a variety of animal species. The efficacy of L-826,141 is also demonstrated in different in vivo models.
- Frenette, Richard,Blouin, Marc,Brideau, Christine,Chauret, Nathalie,Ducharme, Yves,Friesen, Richard W.,Hamel, Pierre,Jones, Tom R.,Laliberte, France,Li, Chun,Masson, Paul,McAuliffe, Malia,Girard, Yves
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p. 3009 - 3013
(2007/10/03)
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- Discovery of L-791,943: a potent, selective, non emetic and orally active phosphodiesterase-4 inhibitor.
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Structure-activity relationship studies directed toward improving the potency and metabolic stability of CDP-840 (3) resulted in the discovery of L-791,943 (11n) as a potent (HWB TNF-alpha = 0.67 microM) and orally active phosphodiesterase type 4 (PDE4) inhibitor. This compound, which bears a stable bis-difluoromethoxy catechol and a pendant hexafluorocarbinol, exhibited a long half-life in rat and in squirrel monkey. It is well tolerated in ferret with an emetic threshold greater than 30 mg/kg (po) and was found to be active in the ovalbumin-induced bronchoconstriction model in guinea pig and in the ascaris-induced bronchoconstriction models in sheep and squirrel monkey.
- Guay, Daniel,Hamel, Pierre,Blouin, Marc,Brideau, Christine,Chan, Chi Chung,Chauret, Nathalie,Ducharme, Yves,Huang, Zheng,Girard, Mario,Jones, Tom R,Laliberte, France,Masson, Paul,McAuliffe, Malia,Piechuta, Hanna,Silva, Jose,Young, Robert N,Girard, Yves
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p. 1457 - 1461
(2007/10/03)
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- Improving metabolic stability of phosphodiesterase-4 inhibitors containing a substituted catechol: Prevention of reactive intermediate formation and covalent binding
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A detailed study directed towards metabolic stability optimization of the alkoxy substituents on the catechol moiety of CDP-840 is reported. Replacement of the methoxy and cyclopentyloxy substituents by cyclobutyloxy and/or difluromethoxy groups resulted in the discovery of potent and selective PDE4 inhibitors where the formation of reactive metabolites that could covalently bind to microsomal protein was significantly reduced or eliminated.
- Chauret, Nathalie,Guay, Daniel,Li, Chun,Day, Stephen,Silva, José,Blouin, Marc,Ducharme, Yves,Yergey, James A.,Nicoll-Griffith, Deborah A.
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p. 2149 - 2152
(2007/10/03)
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